Cellular responses to growth factors and cytokines are characterized by the activation of signal transduction pathways, including the signal transducer and activator of transcription (Stat) family of cytoplasmic transcription factors (1-4). Activation of Stat proteins is initiated upon their tyrosine phosphorylation, a key event in the formation of phosphotyrosine-SH2 (pTyr-SH2) interactions and the dimerization between two Stat monomers. In turn, dimers of Stats translocate to the nucleus and bind to specific DNA-response elements and induce the transcription of genes essential for cellular responses. Physiological functions of Stats include cell proliferation, differentiation, development and apoptosis (reviewed in (5-10)).
In contrast to the finite kinetics of normal Stat signaling, constitutive activation of Stat3 and Stat5 is frequently observed in human tumors (11, 12) and has been linked to tumor progression. Aberrant Stat3 signaling is detected in breast cancer, prostate cancer, head and neck squamous cell carcinoma, as well as in lymphomas and leukemias (13-20, reviewed in 21-28). In malignant cell lines and tumors that harbor constitutively active Stat3, studies also show an overexpression of Stat3-regulated genes, including anti-apoptotic Bcl-xL, Mcl-1, Bcl-2, and survivin, cell cycle regulators, Cyclin D1 and D2, angiogenesis factor, VEGF, and altered expression of immune-modulatory factors (15, 16, 18, 20). These abnormal changes lead to the dysregulated biological processes, cell cycle, survival and angiogenesis, and the repressed host immune functions (reviewed in (27, 28) that contribute to oncogenic transformation. Thus, the inhibition of abnormal Stat3 signaling alone is sufficient to repress the induction of these genes, resulting in cell cycle arrests and apoptosis of malignant cells (15, 18, 20, 29), sensitization of tumor cells to chemotherapy-induced apoptosis (30), and tumor regression (29). Small-molecule inhibitors of Stat3 therefore have the potential to impact tumors that harbor constitutively active Stat3.
Some studies have established constitutive activation of Stat3 as one of the molecular changes that is required for tumor development and progression. Other studies have implicated signal transduction components in the antitumor cell activity of platinum complexes. There is evidence to suggest the modulation by cisplatin of members of the mitogen-activated protein kinase family and PI-3-kinase/Akt (31-34). Importantly, cisplatin does not have an effect on Stat3 activity. Although a compound may contain platinum, the effect of each platinum-containing compound on malignant cells differs, thus making it difficult to predict how effective a certain platinum-containing compound will be on a particular type of cancer a priori. Nonetheless, the wide therapeutic application of cisplatin in solid tumors (34, 51) and the importance of constitutively active Stat3 in malignant transformation together make the present invention of great significance in its exploration of the biochemical and biological properties of IS3 295 as a Stat3 inhibitor.
A previous study reported that a different class of platinum complexes inhibited Stat3 signaling and induced tumor regression (35). The current invention improves upon the report (35) and investigated the modulation of Stat3 by a different platinum compound and how this contributes to the anti-tumor cell activity in vivo.